Glioblastoma multiforme (GBM) is the most common and lethal primary malignancy of the central nervous system (CNS), with an annual incidence of ˜190.000 new cases.
GBM are tumors of the neuroepithelial tissue, attributed to the group of astrocytic tumors and classified by the World Health Organization (WHO) as a grade IV glioma. The designation WHO grade IV is assigned to cytologically malignant, mitotically active, necrosis-prone neoplasms typically associated with rapid pre- and postoperative disease evolution and a fatal outcome.
The current standard of care for patients with GBM includes surgical resection, followed by a combination of radiation therapy (RT) to the resection cavity and chemotherapy with temozolomide (TMZ) and a consecutive treatment with several adjuvant cycles of TMZ.
Surgical resection alone results in a median survival of approximately 6 months. Combined, surgical resection and RT extend median survival to 12.1 months. Addition of TMZ further extends the median survival to 14.6 months.
Beside the proven benefit of surgical resection and aggressive treatment with chemo- and radiotherapy, the prognosis remains very poor. As an alternative modality of treatment novel therapeutic approaches were developed including targeted therapies, immunotherapies and gene therapy.
Immunotherapy is one of the most elegant concepts in cancer therapy. The central idea is based on recruiting and restoring reactivity of the host's immune system to combat cancer. Several immotherapeutical approaches have been successfully introduced into the clinic and have emerged as the most promising therapeutics in oncology. The limiting factor regarding the development of therapeutical vaccines is the identification of tumor-associated antigens.
Tumor cells biologically differ substantially from their nonmalignant cells of origin. These differences are due to genetic alterations acquired during tumor development and result, inter alia, also in the formation of qualitatively or quantitatively altered molecular structures in the cancer cells. Furthermore tumor cells may also induce surrounding stroma cells to propagate cancer progression by regulating local cytokine levels, which results in altered molecular structures in these genetically unchanged stroma cells differing from non cancerous tissues. Tumor associated structures of this kind, which are recognized by the specific immune system of the tumor-harboring host, are referred to as tumor-associated antigens. The specific recognition of tumor-associated antigens involves cellular and humoral mechanisms which are two functionally interconnected units: CD4+ and CD8+T-lymphocytes recognize the processed antigens presented on the molecules of the MHC (major histocompatibility complex) classes II and I, respectively, while B lymphocytes produce circulating antibody molecules which bind directly to unprocessed antigens. The potential clinical-therapeutical importance of tumor-associated antigens results from the fact that the recognition of antigens on neoplastic cells by the immune system leads to the initiation of cytotoxic effector mechanisms and, in the presence of T helper cells, can cause elimination of the cancer cells (Pardoll, Nat. Med. 4:525-31, of the 1998).
There is a need in the art for genetic markers and targets of tumors of the central nervous system (CNS) such as glioma, in particular glioblastoma, allowing the design of specific, reliable and sensitive diagnostic and therapeutic approaches of these diseases.
The invention relates to the therapy and diagnosis of tumors of the central nervous system such as glioma, in particular glioblastoma. In particular, the invention relates to the identification of molecular structures that are associated with tumors of the central nervous system such as glioma, in particular glioblastoma, and can serve as targets for diagnostic and therapeutic approaches of these diseases.